This invention relates to methods and compositions useful for decreasing the rate of metabolism of heme in mammals. More specifically, it relates to the use of metal protoporphyrins IX to decrease the rate at which heme is metabolized in living mammals.
Iron protoporphyrin, also called heme, or more accurately ferroprotoporphyrin IX, is the specific porphyrin isomer found in mammalian whole blood. It is an essential component in the respiratory chain and in the energy transfer reactions which take place in the mammalian body. It is synthesized and degraded by known metabolic routes involving known enzymatic reactions.
In the normal course of degradation, heme first undergoes a ring opening reaction to form biliverdin which then converts to bilirubin. Bilirubin is toxic, but normally this toxicity is not manifested since it rapidly combines with albumin and is transported to the liver. In the liver, the protein is released and the bilirubin is converted to the corresponding diglucuronide by reaction with uridine diphosphoglucuronate. The diglucuronide is soluble and excreted.
A number of synthetic analogs of iron protoporphyrin IX are known. They are commercially available or are readily synthesized by known methods. These include, for example, platinum, zinc, nickel, cobalt, copper, silver, manganese, chromium and tin protoporphyrin IX. For convenience herein, these compounds are referred to generically as Me-protoporphyrin, where Me stands for metal, and specifically by utilizing the chemical symbol for the metal such as Cr-protophorphyrin and Sn-protophorphyrin for the chromium and tin compounds respectively.
One of the more difficult aspects of the toxicity of bilirubin is the so-called jaundice of the newborn which arises from an undesirably high concentration of bilirubin in the blood of newborn mammals. In the period immediately after birth, there is a high concentration of heme in mammalian blood. There is also a high degree of heme oxygenase activity. This enzyme is essential to the metabolism of heme to bilirubin. The combination of factors leads to rapid metabolism of large amounts of heme and results in high concentrations of bilirubin in the body fluids of neonates. Since bilirubin is yellow, the infant appears yellow. Hence, the name jaundice of the newborn.
Free bilirubin is fat soluble and readily crosses the blood-brain barrier causing extensive and serious brain damage. One manifestation of the toxicity of bilirubin is kernicterus or bilirubin encephalopathy. It may present clinically as lethargy, rigidity, opisthotonus, high-pitched cry, fever and convulsions. It may result in death. Survivors often have cerebral palsy, frequently of the choreoathetoid type, deafness, mental retardation and other neurologic defects in infancy or early childhood.
The principal treatments for hyperbilirubinemia have been phototherapy and exchange transfusions. In the former treatment, the patient is exposed to increased intensities of light in the visible range particularly between 420 and 470 nm. This results in increased oxidation of bilirubin or conversion by other mechanisms to products that are not yet fully identified. The treatment is widespread, particularly in the United States, but is not regarded as fully satisfactory since there are many as yet unanswered questions concerning its safety and effectiveness.
The more traumatic procedure of exchange transfusion is indicated with full term infants when there is an unconjugated bilirubin level of 20 mg/dl. With premature infants, the transfusion may be considered necessary at concentrations as low as 9 mg/dl. It is now generally accepted that concentrations which do not exceed 2.0 mg/dl can be tolerated without unnecessary damage to the infant. However, it appears clearly to be desirable to keep the level of this highly toxic chemical lower than 2 mg/dl if possible.
Increased concentrations of bilirubin often appear in the blood of adult humans and other mammals with sickle cell anemia, thalassemia and other congenital anemias as well as with animals and humans with acquired liver diseases. With such individuals, the concentration of bilirubin rarely reaches the high levels observed with neonates. It does, however, reach levels which may be toxic and should be controlled.
It is desirable, therefore, to have available methods and materials for inhibiting the metabolism of heme so as to decrease the rate at which it degrades and the rate at which bilirubin accumulates in the blood.